Damping of dopamine (DA) overactivity by the use of DA-receptor blocking drugs is today the most important principle in the treatment of schizophrenia. "Classical neuroleptics" such as haloperidol, cis(Z)flupentixol or chlorpromazine induce antipsychotic effect via DA-receptor blockade. Pharmacologically, such compounds antagonize stereotypies induced by dopaminergic compounds (i.e. methylphenidate, apomorphine, amphetamine) in mice or rats. Unfortunately, the incidence of severe extrapyramidal side effects (EPS) (dystonia, akathisia and parkinsonism) is very frequent in long term treatment with these neuroleptics and causes great concern among clinicians. The EPS are difficult to treat, and unsuccessful treatment often leads to poor medication compliance. Some of these neurological side effects, which generally involve involuntary movement disorders, have been correlated to the propensity of the drugs to induce catalepsy in rats (Arnt. et al., Neuropharmacology 20, 1331-1334 (1981).
A class of compounds, which does not produce EPS and which is effective in the treatment of schizophrenic disorders, is termed "atypical neuroleptics". Clozapine is the prototype of such drugs. Clozapine is an effective antipsychotic in man but, due to severe incidences of agranulocytosis it is rarely used clinically. Pharmacologically clozapine induces no catalepsy in rats, neither does it inhibit stereotypies induced by dopaminergic aganists in rodents. Clozapine blocks central serotonergic and noradrenergic receptors in animal studies.
In recent years several reports have suggested that inhibition of the spontaneous firing activity of DA neurones in ventral tegmental area (VTA) in the rat brain upon repeated treatment with a neuroleptic is indicative of the antipsychotic potential of the compound, whereas inhibition of the activity in substantia nigra pars compacta (SNC) should account for the development of EPS (Bunney and Grace, Life Science 25, 1715-1725 (1978), White and Wang, Science 221, 1054-1057 (1983), Chiodo and Bunney, J.Neuroscience 5, 2539-2544 (1985), Skarsfeldt, Life Science 42, 1037-1044 (1988)). "Classical neuroleptics" are active in both areas in the same dose range while "atypical neuroleptics" mainly inactivate DA-neurons in the VTA area. Clozapine has been shown to be active only in the VTA area.
U.S. Pat. No. 4,710,500 discloses a class of optionally 5-substituted 1-aryl-3-piperdinyl-, 1-aryl3-[1,2,3,6-tetrahydropyridinyl]- or 1-aryl-3-piperazinyl-indol derivatives having potent dopamine antagonist activity in vivo and in vitro, as tested in pharmacological tests. The tests used were methylphenidate antagonism, catalepsy and .sup.3 H-spiroperidol binding tests. Accordingly, the compounds of U.S. Pat. No. 4,710,500 have been shown having "Classically neuroleptic activity".